A novel first-in-class gene-regulation therapy for Dravet syndrome was associated with large reductions in seizures and improved functional outcomes in children with Dravet syndrome.

Results from phase 1/2a trials of zorevunersen and ongoing open label extension studies showed that children receiving the highest dose of the drug experienced up to a 91% reduction in seizure frequency along with improvements in communication, behavior, and quality of life.

“One of the most important improvements [in these trials] is in the expressive and receptive language domains. A child/adolescent’s ability to communicate will improve socialization, behavior, and ability to learn,” Linda Laux, MD, co-lead study investigator, and head of the Epilepsy Center at Ann & Robert H. Lurie Children’s Hospital of Chicago and associate professor of pediatrics at Northwestern University Feinberg School of Medicine, in Chicago, told Medscape Medical News: 

The study was published online on March 4 in the New England Journal of Medicine.

A Medically Refractory Population 

Dravet syndrome is a rare epilepsy that begins in infancy and is most often caused by mutations in the SCN1A gene, leading to severe seizures, developmental delays, and an increased risk of sudden unexpected death in epilepsy (SUDEP).

Dravet syndrome is a rare type epilepsy that typically begins in infancy and is most often caused by SCN1A mutations and associated with severe seizures, developmental delays, and an increased risk of SUDEP.

Despite newer therapies such as fenfluramine and Epidiolex (Jazz Pharmaceuticals), a formulation of purified cannabidiol, many patients with Dravet syndrome continue to experience refractory seizures. 

In addition, these approved treatments focus on seizure reduction but do not address the underlying genetic defect or lead to sustained improvements in cognitive and developmental outcomes.

Zorevunersen (formerly STK-001), which is administered via injection into the spinal fluid, is a mechanistically distinct gene-regulation approach designed to boost production of the missing SCN1A protein from the healthy copy of the gene. The goal is to restore more normal brain activity and potentially change the course of the disease.

The investigators describe this strategy as gene regulation rather than gene replacement. This is an approach designed to correct haploinsufficiency without introducing exogenous genetic material.

To evaluate the safety and potential efficacy of this approach, investigators conducted two phase 1/2a open-label, multicenter trials — MONARCH in the United States and ADMIRAL in the United Kingdom. These trials included 81 children aged 2-18 years with genetically confirmed Dravet syndrome who were on stable antiseizure medication regimens.

At baseline, participants had a baseline average of approximately 17 seizures per month and were considered medically refractory. 

A Dose-Response Relationship 

The MONARCH study, some children received a single dose of zorevunersen at escalating levels (10-70 mg) to evaluate safety, whereas others received multiple doses (20-45 mg) administered about 1 month apart.

In the ADMIRAL study, children received multiple doses of zorevunersen (30-70 mg) administered over several weeks, while a small group at the highest dose received only two doses to evaluate whether a reduced dosing schedule was effective. 

Seventy-five patients continued in open label extension studies, SWALLOWTAIL (US) and LONGWING (UK), receiving maintenance dosing of 45 mg every 4 months. This allowed the investigators to assess its long-term effects through 20 months and, in some cases, beyond 36 months.

The study’s primary endpoints were safety and tolerability. Secondary and exploratory outcomes included 28-day convulsive seizure frequency, Clinical Global Impression of Change (CGI-C), Caregiver Global Impression of Change, EQ-5D-Y quality-of-life scores, and adaptive behavior assessed using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3).

Nearly all participants experienced at least one treatment-emergent adverse event (TEAE), though most were mild to moderate.

In the phase 1/2a trials, the most common TEAE was post-lumbar puncture syndrome (25%). In the extension studies, the most frequent event was elevated cerebrospinal fluid (CSF) protein (45%). Importantly, no reported cases of hydrocephalus or increased intracranial pressure were associated with elevated CSF protein levels. 

Serious TEAEs occurred in 22% of children during the phase 1/2a trials and 29% during extension follow-up, with only one serious event deemed as treatment related.

Two deaths from SUDEP and one from malnutrition occurred and were attributed to underlying disease rather than the study drug.

The majority of adverse effects were attributable to the lumbar puncture procedure or to elevated CSF protein levels without clinical consequences. Based on these observations, the team proceeded with two 70-mg doses followed by a 45-mg maintenance dose, said co-lead investigator Helen Cross, PhD, director and professor of childhood epilepsy at the UCL Great Ormond Street Institute of Child Health in London. However, she noted that one serious and unexpected event occurred after the first three 70-mg doses, with no other identifiable cause.

Children who received two to three 70-mg doses experienced reductions in motor seizures of nearly 85% at 3 months and 73% at 6 months compared with baseline. In extension studies, seizure reductions ranged from 58% to 90% during the first 20 months, with some patients maintaining benefits for more than 36 months.

The investigators reported a consistent dose-response relationship, with higher doses associated with greater seizure reduction.

Beyond Seizure Control 

Children also experienced meaningful improvements in expressive and receptive language, communication, social interactions, and adaptive behavior, suggesting that addressing the underlying genetic cause may also improve cognitive and developmental outcomes, not just seizures.

Vineland-3 analyses demonstrated improvements in communication among participants treated for more than 36 months. Clinician and caregiver CGI-C assessments indicated that most children were rated as minimally, much, or very much improved at higher doses.

Laux noted that prior research has consistently identified expressive and receptive language as the most important areas of improvement on adaptive behavior scales, according to both parents and clinicians. He emphasized that strengthening a child’s ability to communicate can enhance socialization, behavior, and learning potential.

These gains were reflected not only in clinical assessments but also in caregiver reports, including that of Lauren Truelove, the mother of Freddie, an 8-year-old study participant.

“The trial has completely changed our lives. We now have a life we didn’t ever think was possible and most importantly it’s a life that Freddie can enjoy.”

However, the investigators caution that the open-label design, small sample size, and potential caregiver bias warrant careful interpretation of developmental outcomes.

Phase 3 Trial Underway 

A phase 3, randomized, double-blind, placebo-controlled trial is currently underway to further evaluate whether zorevunersen can provide sustained long-term benefits for children with Dravet syndrome. 

The trial’s primary endpoint is seizure reduction. Secondary outcomes include scores on the Vineland-3 scales; cognitive, language, behavior, and motor outcomes; and ongoing safety assessments. 

Laux said that for zorevunersen to be considered a disease-modifying therapy for Dravet syndrome, it would need to demonstrate improvements not only in seizure control but also in associated comorbidities, including cognition, language, behavior, and motor function. 

Early data from ongoing extension studies are “very promising,” said Laux, with durable seizure reductions and improvements across Vineland-3 adaptive behavior scale subdomains — promising findings that may signal continued progress in this patient population. 

Cross agreed that, although longer-term data beyond 36 months are still pending, the early signals are positive.

She noted that the double-blind, placebo-controlled design will provide critical evidence in determining whether zorevunersen can truly alter disease course. Demonstrating sustained seizure reductions along with improvements in developmental measures will be key to establishing whether the therapy is disease-modifying. 

A Potential “Unprecedented” Advance 

In an accompanying editorial led by Gemma L. Carvill, PhD, of Northwestern University Feinberg School of Medicine, and Heather C. Mefford, MD, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee, noted that if these early results are confirmed in randomized trials, seizure reductions approaching 80% would represent an “unprecedented” advance for this patient population. 

They also highlighted the broader potential of splice-modulating antisense therapies to treat other genetic disorders caused by haploinsufficiency involving poison exons.

“In the meantime, the results of ongoing trials of zorevunersen in Dravet syndrome are eagerly awaited,” the editorialists wrote.

The study was funded by Stoke Therapeutics. Laux reports consulting for BIOCODEX and Stoke Therapeutics. Cross reports receiving research support through grants/contracts from Great Ormond Street Hospital and Epygenix Therapeutics; serving as principal/clinical investigator for Stoke Therapeutics and Ultragenyx Pharmaceutical; serving on advisory/educational roles with BIOCODEX, Jazz Pharmaceuticals, and UCB. All remuneration paid to her department or institution. Carvill reports consulting for BridgeBio and Stoke Therapeutics. Mefford reports no relevant financial disclosures.